The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy

Abstract

Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly vibrant movement and distribution of mitochondria within cells is controlled by the highly coordinated interplay between mitochondrial dynamic processes and fission and fusion events, as well as mitochondrial quality-control processes, mainly mitochondrial autophagy (also known as mitophagy). Fusion connects and unites neighboring depolarized mitochondria to derive a healthy and distinct mitochondrion. In contrast, fission segregates damaged mitochondria from intact and healthy counterparts and is followed by selective clearance of the damaged mitochondria via mitochondrial specific autophagy, i.e., mitophagy. Hence, the mitochondrial processes encompass all coordinated events of fusion, fission, mitophagy, and biogenesis for sustaining mitochondrial homeostasis. Accumulated evidence strongly suggests that mitochondrial impairment has already emerged as a core player in the pathogenesis, progression, and development of various human diseases, including cardiovascular ailments, the leading causes of death globally, which take an estimated 17.9 million lives each year. The crucial factor governing the fission process is the recruitment of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, from the cytosol to the outer mitochondrial membrane in a guanosine triphosphate (GTP)-dependent manner, where it is oligomerized and self-assembles into spiral structures. In this review, we first aim to describe the structural elements, functionality, and regulatory mechanisms of the key mitochondrial fission protein, Drp1, and other mitochondrial fission adaptor proteins, including mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics 49 (Mid49), and mitochondrial dynamics 51 (Mid51). The core area of the review focuses on the recent advances in understanding the role of the Drp1-mediated mitochondrial fission adaptor protein interactome to unravel the missing links of mitochondrial fission events. Lastly, we discuss the promising mitochondria-targeted therapeutic approaches that involve fission, as well as current evidence on Drp1-mediated fission protein interactions and their critical roles in the pathogeneses of cardiovascular diseases (CVDs).

Drp1-JNKknockdown mitigates Scribble loss induced cell proliferation, metastasis and lethality phenotypes inDrosophila

“…Overall, Scrib plays a role in maintaining the cell polarity and cell proliferation regulation by blocking the Drp1 and JNK which regulate mitochondrial dynamics, via maintaining the mitochondrial membrane polarity, morphology and oxidative stress. Mitochondria, a dynamic double membrane-bound cell organelles, play crucial role in ATP production, recently emerged as hub for Drp-1 mediated mitochondrial fission protein interactome connective pathways for various diseases [50]. Our results clearly show that upon knockdown of Scrib leads to enhanced Drp-1 mediated disruption of mitochondrial dynamics, which induces enhanced ROS production and cause reduced ATP production leading to increased cell proliferation and metastasis.…”

“…These two mitochondrial regulators encode a dynamin-family GTPase, to maintain the mitochondrial morphology and activity [11]. The Drp1 migrates from cytosol to mitochondrial outer membrane (MOM) and forms anoligomeric collar like structure around the mitochondrion and hydrolyzes GTP to execute Drp1 -mediated mitochondrial fission event [12, 13].…”

Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer

“…Mitochondrial fission is the process by which a mitochondrion fragmentates into smaller mitochondria. DRP1 is a GTP-hydrolyzing enzyme that plays a crucial role in mediating mitochondrial fission [ 52 , 53 ]. DRP1 and its receptors—mitochondrial fission protein 1 (FIS1), mitochondrial dynamics proteins of 49 and 51 kilodaltons (Mid49/51), and mitochondrial fission factor (MFF)—regulate mitochondrial fission [ 54 ].…”

Selective inhibitors targeting Fis1/Mid51 protein-protein interactions protect against hypoxia-induced damage in cardiomyocytes

“…It was suggested that Fis1/Mid51 PPI results in increased mitochondrial pathological fission ( Zhao et al, 2011 ; Vásquez-Trincado and Schinkel, 2016 ; Liu et al, 2023 ). Moreover, imbalanced mitochondrial dynamics were demonstrated to lead to a number of human pathologies, such as CVDs ( Zerihun et al, 2023 ). Therefore, an inhibitor of this interaction may decrease mitochondrial fission and potentially have therapeutic utility.…”